Indolocarbazole anticancer agents and methods of using them

A compound of the general formula II:

• wherein
• R1 and R2 independently represent H, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl, or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl or R1 and R2 combine to form a methylenedioxy, ethylenedioxy, propylenedioxy or a butylenedioxy group wherein one or more of the carbon atoms may be substituted with F, Cl, Br, I, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or a heterocycle;
• R3 represents X, CO—X, (CH2)1-6-X, NHX, NX2, NH(CH2)1-6-X, NHCOX, or NHCO(CH2)1-6-X wherein X represents H, OH, NH2, CN, CHO, 2-hydroxy butyl, 3-sulfolane, 2-hydroxymethyl-3-hydroxypropyl, sulfonyl, mono- or polyfluorinated C1-8 alkyl, (C1-8)alkyl, C1-8 alkoxy, cyclo(C3-6)alkyl, hydroxy(C1-6)alkyl, hydroxy(C1-6)alkoxy, dihydroxy(C1-6)alkyl, aryloxy, aryl, heterocycle, glyconyl, mannonyl, gulonyl, glycuronyl, guluronyl, mannuronyl, or (ethylmorpholinyl;
• R4 represents H, NH2, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or heterocycle;
• or
• a pharmaceutically acceptable salt thereof.

A method of inhibiting topoisomerase I activity comprising administering to a mammal in need of inhibition of topoisomerase I activity an effective amount of at least one indolocarbazole analogue of the general formula I:

• wherein
• R1 and R2 independently represent H, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl, or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl or R1 and R2 combine to form a methylenedioxy, ethylenedioxy, propylenedioxy or a butylenedioxy group wherein one or more of the carbon atoms may be substituted with F, Cl, Br, I, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or a heterocycle;
• R3 represents X, CO—X, (CH2)1-6-X, NHX, NX2, NH(CH2)1-6-X, NHCOX, or NHCO(CH2)1-6-X wherein X represents H, OH, NH2, CN, CHO, 2-hydroxy butyl, 3-sulfolane, 2-hydroxymethyl-3-hydroxypropyl, sulfonyl, mono- or polyfluorinated C1-8 alkyl, (C1-8)alkyl, C1-8 alkoxy, cyclo(C3-6)alkyl, hydroxy(C1-6)alkyl, hydroxy(C1-6)alkoxy, dihydroxy(C1-6)alkyl, aryloxy, aryl, heterocycle, glyconyl, mannonyl, gulonyl, glycuronyl, guluronyl, mannuronyl, or ethylmorpholinyl;
• R4 represents H, NH2, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or heterocycle;
• or
• a pharmaceutically acceptable salt thereof. alone or in combination with a carrier.

A method of inhibiting topoisomerase I activity comprising administering to a mammal in need of inhibition of topoisomerase I activity an effective amount of at least one indolocarbazole analogue of the general formula II:

• wherein
• R1 and R2 independently represent H, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl, or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl or R1 and R2 combine to form a methylenedioxy, ethylenedioxy, propylenedioxy or a butylenedioxy group wherein one or more of the carbon atoms may be substituted with F, Cl, Br, I, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or a heterocycle;
• R3 represents X, CO—X, (CH2)1-6-X, NHX, or NX2, NH(CH2)1-6-X, NHCOX, or NHCO(CH2)1-6-X wherein X represents H, OH, NH2, CN, CHO, 2-hydroxy butyl, 3-sulfolane, 2-hydroxymethyl-3-hydroxypropyl, sulfonyl, mono- or polyfluorinated C1-8 alkyl, (C1-8)alkyl, C1-8 alkoxy, cyclo(C3-6)alkyl, hydroxy(C1-6)alkyl, hydroxy(C1-6)alkoxy, dihydroxy(C1-6)alkyl, aryloxy, aryl, heterocycle, glyconyl, mannonyl, gulonyl, glycuronyl, guluronyl, mannuronyl, or ethylmorpholinyl;
• R4 represents H, NH2, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or heterocycle;
• or
• a pharmaceutically acceptable salt thereof, alone or in combination with a carrier.

A composition for inhibiting topoisomerase I activity comprising an effective amount of at least one compound of the general formula I:

• wherein
• R1 and R2 independently represent H, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl, or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl or R1 and R2 combine to form a methylenedioxy, ethylenedioxy, propylenedioxy or a butylenedioxy group wherein one or more of the carbon atoms may be substituted with F, Cl, Br, I, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or a heterocycle;
• R3 represents X, CO—X, (CH2)1-6-X, NHX, NX2, NH(CH2)1-6-X, NHCOX, or NHCO(CH2)1-6-X wherein X represents H, OH, NH2, CN, CHO, 2-hydroxy butyl, 3-sulfolane, 2-hydroxymethyl-3-hydroxypropyl, sulfonyl, mono- or polyfluorinated C1-8 alkyl, (C1-8)alkyl, C1-8 alkoxy, cyclo(C3-6)alkyl, hydroxy(C1-6)alkyl, hydroxy(C1-6)alkoxy, dihydroxy(C1-6)alkyl, aryloxy, aryl, heterocycle, glyconyl comprising gluconyl, mannonyl, gulonyl, glycuronyl comprising glucuronyl, guluronyl, mannuronyl, or ethylmorpholinyl;
• R4 represents H, NH2, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or heterocycle;
• or
• a pharmaceutically acceptable salt thereof, in combination with a carrier or a pharmaceutical adjuvant or additive material.

A composition for inhibiting topoisomerase I activity comprising an effective amount of at least one compound of the general formula II:

• wherein
• R1 and R2 independently represent H, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl, or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl or R1 and R2 combine to form a methylenedioxy, ethylenedioxy, propylenedioxy or a butylenedioxy group wherein one or more of the carbon atoms may be substituted with F, Cl, Br, I, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or a heterocycle;
• R3 represents X, CO—X, (CH2)1-6-X, NHX, NX2, NH(CH2)1-6-X, NHCOX, or NHCO(CH2)1-6-X wherein X represents H, OH, NH2, CN, CHO, 2-hydroxy butyl, 3-sulfolane, 2-hydroxymethyl-3-hydroxypropyl, sulfonyl, mono- or polyfluorinated C1-8 alkyl, (C1-8)alkyl, C1-8 alkoxy, cyclo(C3-6)alkyl, hydroxy (C1-6)alkyl, hydroxy (C1-6)alkoxy, dihydroxy (C1-6)alkyl, aryloxy, aryl, heterocycle, glyconyl mannonyl, gulonyl, glycuronyl guluronyl, mannuronyl, or ethylmorpholinyl;
• R4 represents H, NH2, C1-6 alkyl, aryl-C1-6 alkyl, mono- or polyfluorinated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, cyclo(C3-6)alkyl, aryl or heterocycle;
• or
• a pharmaceutically acceptable salt thereof, in combination with a carrier or a pharmaceutical adjuvant or additive material.